U.S. patent number 9,422,364 [Application Number 13/581,245] was granted by the patent office on 2016-08-23 for immunoglobulin preparation and storage system for an immunoglobulin preparation.
This patent grant is currently assigned to CSL Behring AG. The grantee listed for this patent is Reinhard Franz Bolli, Liane Hoefferer, Peter Lerch, Werner Maeder, Renzo Pedrussio. Invention is credited to Reinhard Franz Bolli, Liane Hoefferer, Peter Lerch, Werner Maeder, Renzo Pedrussio.
United States Patent |
9,422,364 |
Maeder , et al. |
August 23, 2016 |
Immunoglobulin preparation and storage system for an immunoglobulin
preparation
Abstract
The present invention relates to an immunoglobulin preparation
comprising immunoglobulin in a mass-volume percentage of at least
4%, wherein the concentration of oxygen dissolved in the
preparation at room temperature is less than 40 .mu.mol/l.
Inventors: |
Maeder; Werner (Oftringen,
CH), Bolli; Reinhard Franz (Gumligen, CH),
Lerch; Peter (Bern, CH), Pedrussio; Renzo
(Liebefeld, CH), Hoefferer; Liane (Ostermundigen,
CH) |
Applicant: |
Name |
City |
State |
Country |
Type |
Maeder; Werner
Bolli; Reinhard Franz
Lerch; Peter
Pedrussio; Renzo
Hoefferer; Liane |
Oftringen
Gumligen
Bern
Liebefeld
Ostermundigen |
N/A
N/A
N/A
N/A
N/A |
CH
CH
CH
CH
CH |
|
|
Assignee: |
CSL Behring AG (Bern,
CH)
|
Family
ID: |
42321007 |
Appl.
No.: |
13/581,245 |
Filed: |
February 24, 2011 |
PCT
Filed: |
February 24, 2011 |
PCT No.: |
PCT/EP2011/052770 |
371(c)(1),(2),(4) Date: |
September 18, 2012 |
PCT
Pub. No.: |
WO2011/104315 |
PCT
Pub. Date: |
September 01, 2011 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20130017191 A1 |
Jan 17, 2013 |
|
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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61282548 |
Feb 26, 2010 |
|
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Foreign Application Priority Data
|
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|
|
Feb 26, 2010 [EP] |
|
|
10001996 |
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07K
16/06 (20130101); A61K 39/395 (20130101); A61P
37/02 (20180101); A61K 39/39591 (20130101); A61P
37/00 (20180101); A61K 9/0019 (20130101); C07K
2317/35 (20130101); A61K 2039/54 (20130101); C07K
2317/94 (20130101); C07K 2317/21 (20130101) |
Current International
Class: |
A61K
39/395 (20060101); C07K 16/06 (20060101); A61K
9/00 (20060101) |
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WO |
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Apr 2008 |
|
WO |
|
WO 2011/095543 |
|
Aug 2011 |
|
WO |
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|
Primary Examiner: Kim; Yunsoo
Attorney, Agent or Firm: McNeill Baur PLLC
Parent Case Text
This application is the United States national stage of
PCT/EP2011/052770, filed Feb. 24, 2011, (published as WO
2011/104315), and also claims priority to European Patent
Application No. 10 001 996.7, filed Feb. 26, 2010, and U.S.
Provisional Application No. 61/282,548, filed Feb. 26, 2010, all of
which are incorporated herein by reference.
Claims
The invention claimed is:
1. A ready-to-use liquid immunoglobulin preparation for intravenous
or subcutaneous administration comprising immunoglobulin in a
mass-volume percentage of at least 4%, wherein the concentration of
oxygen dissolved in the preparation at room temperature is less
than 200 .mu.mol/l, wherein the absorbance at 350 nm minus the
absorbance at 500 nm (absorbance A.sub.350-500 nm) of the
immunoglobulin preparation remains below 0.28 upon storage for 24
months at 25.degree. C. in the dark, and wherein the preparation is
comprised within a container with a headspace occupied by a gas
other than air, wherein the content of oxygen in the gas of the
headspace remains less than 20 vol-% during said storage.
2. The immunoglobulin preparation according to claim 1, wherein the
concentration of oxygen dissolved in the preparation at room
temperature is less than 175 .mu.mol/l.
3. The immunoglobulin preparation according to claim 1, wherein the
immunoglobulin preparation comprises immunoglobulin in a
mass-volume percentage of at least 5%.
4. The immunoglobulin preparation according to claim 1, wherein the
immunoglobulin comprised in the immunoglobulin preparation consists
essentially of IgG.
5. The immunoglobulin preparation according to claim 1, wherein the
preparation has a mean increase in absorbance A.sub.350-500 nm of
less than 0.2 upon storage of 6 months at 37.degree. C. in the
dark.
6. Storage system for a ready-to-use liquid immunoglobulin
preparation for intravenous or subcutaneous administration
comprising a container having an interior, a first portion of said
interior being occupied by the ready-to-use liquid immunoglobulin
preparation comprising immunoglobulin in a mass-volume percentage
of at least 4%, and the remaining portion of said interior forming
a headspace and being occupied by a gas other than air, wherein the
content of oxygen in the gas of the headspace is less than 20
vol-%, and wherein the absorbance A.sub.350-500 nm of the
immunoglobulin preparation in the container remains below 0.28 upon
storage for 24 months at 25.degree. C. in the dark.
7. The storage system according to claim 6, wherein the content of
oxygen in the gas of the headspace is less than 16 vol-%.
8. The storage system according to claim 6, wherein the gas of the
headspace is at approximately atmospheric or higher than
atmospheric pressure.
9. The storage system according to claim 6, wherein the content of
inert gas in the gas of the headspace is more than 80 vol-%.
10. The storage system according to claim 6, wherein the container
is a vial.
11. The storage system according to claim 6, wherein the headspace
and the immunoglobulin preparation are in a volume ratio that
ranges from 0.1:1 to 0.9:1.
12. The storage system according to claim 6, wherein the storage
system has a mean monthly increase of absorbance A.sub.350-500 nm
that is at least 10% lower than the mean monthly increase of
absorbance A.sub.350-500 nm observed when air is used as the gas in
the headspace.
13. Process for preparing a storage system for an immunoglobulin
preparation, comprising filing a container with the immunoglobulin
preparation according to claim 1, filling the container with a gas
other than air, and sealing the container, wherein the gas forms a
headspace above the preparation, and wherein the gas of the
headspace has an oxygen content of less than 20 vol-%.
14. The process according to claim 13, wherein the gas filled into
the container is at atmospheric pressure.
15. The process according to claim 13, wherein the immunoglobulin
preparation comprises immunoglobulin in a solvent, and wherein the
process comprises subjecting the immunoglobulin and/or its solvent
to a degassing step and/or a gassing step using an inert gas.
16. The process according to claim 15, wherein the solvent is
subjected to the degassing and/or gassing step using an inert gas
prior to formulation of the preparation.
17. The immunoglobulin preparation according to claim 1, wherein
the immunoglobulin preparation comprises immunoglobulin in a
mass-volume percentage of 14-20%.
18. The immunoglobulin preparation according to claim 1, wherein
the immunoglobulin preparation comprises immunoglobulin in a
mass-volume percentage of at least 18%.
19. The immunoglobulin preparation according to claim 1, wherein
the immunoglobulin preparation comprises immunoglobulin in a
mass-volume percentage of at least 20%.
Description
The present invention relates to an immunoglobulin (Ig) preparation
with improved stability for storage.
The invention further relates to a storage system for the Ig
preparation, to a process for providing such a storage system and
to the use of a gas having an oxygen content of less than 20 vol-%
for increasing the storage stability of an Ig preparation.
Ig preparations for Ig replacement therapy, e.g. for the treatment
of primary immunodeficiency (PID) disorders, such as common
variable immunodeficiency (CVID) and X-linked agammaglobulinemia,
are widely known in the art. Such Ig preparations are commonly
obtained from human plasma and are stored in vials for further use.
The preparation can then be administered intravenously (IVIg) or
subcutaneously (SCIg) to the patient in need of the therapy.
When using the subcutaneous route, Ig preparations having a
relatively high Ig concentration are desirable, since they allow
for a less frequent administration and/or an administration of
smaller volumes than a preparation of lower concentration.
If stored over several months, known Ig preparations tend to become
yellowish in colour. This effect is particularly pronounced for Ig
preparations having a relatively high Ig concentration and exposed
to stress conditions like light exposure and/or elevated
temperature; said preparations typically show a relatively strong,
yellow-brownish coloration already after storage of two months.
Such a coloration is however in conflict to standard requirements
for Ig preparations. The European Pharmacopoeia, for example,
requires the preparation to remain clear-yellow or light brown.
One possible approach to cope with this problem is to store the Ig
preparation in a dark environment. A further approach is to store
the Ig preparation at a relatively low temperature, for example at
about 5.degree. C. Although both approaches have shown to result in
a reduction of yellowish coloration, they are inconvenient for the
handling and are relatively burdensome to put into practice, since
the respective environment has to be maintained over the whole
storage period.
It is therefore an object of the present invention to provide an Ig
preparation for Ig replacement therapy, which shows a reduced
yellowish coloration and thus allows for complying with the
standard requirements concerning coloration even after prolonged
storage under light and under room temperature. It is a further
object to provide a storage system for storing the preparation in a
manner such that the yellowish coloration is reduced, thus allowing
for complying with the standard requirements concerning coloration
even after prolonged storage under stress conditions like exposure
to light and/or elevated temperature.
The problem is solved by the Ig preparation and the storage system
according to the independent claims. Preferred embodiments are
subject of the dependent claims.
According to a first aspect, the present invention thus relates to
an Ig preparation comprising Ig in a mass-volume percentage of at
least 4% (i.e. 4 g/100 ml). In contrast to naturally occurring
biological fluids, the liquid Ig preparation of the present
invention is thus enriched in Ig. Given its relatively high Ig
concentration, the preparation is suitable for Ig replacement
therapy. Preparations of 10% or more are suitable for subcutaneous
administration which may be performed by the patients
themselves.
It has surprisingly been found that if the concentration of oxygen
dissolved in the preparation at room temperature is less than 200
.mu.mol/l, a high stability against yellowish coloration over a
prolonged period of time can be achieved. Preferably, the yellowish
coloration is caused by stress factors other than light exposure,
i.e. occurs in the dark, is not caused by photodegradation. In
particular, a stable Ig preparation showing only a slight yellowish
coloration or no yellowish coloration at all can be achieved, thus
meeting standard requirements, e.g. of the European Pharmacopoeia,
even after a prolonged storage period of 24 months, even of 36
months, or longer. In particular, a stable Ig preparation meeting
the standard requirements can be achieved, even after a prolonged
storage period of 24 months, even of 36 months, at room temperature
in the dark. The absorbance A.sub.350-500 nm of the stable
immunoglobulin preparation remains below 0.28 upon storage for 24
months at 25.degree. C. in the dark, preferably the stable
immunoglobulin preparation has a concentration of 20% w/v. In a
preferred embodiment of the invention, the absorbance A.sub.350-500
nm remains below 0.355 when measured for a 20% Ig preparation after
storage for 6 months at 37.degree. C. in the dark. The stable
immunoglobulin preparation shows an increase in A.sub.350-500 nm of
less than 0.18, preferably of less than 0.17, even more preferably
of less than 0.16, when stored at 25.degree. C. in the dark for 36
months. The stable immunoglobulin preparation shows an increase in
A.sub.350-500 nm of less than 0.22, preferably of less than 0.20,
even more preferably of less than 0.19, when stored at 37.degree.
C. in the dark for 6 months.
Methods for determining the concentration of oxygen dissolved in
the Ig preparation are well known to the skilled person. For
example, the oxygen concentration can be determined by a
polarographic method, using e.g. a Clark electrode. Alternatively,
also luminescence oxygen sensing can for example be used for
determining the oxygen concentration in the preparation.
When contained in a container, the Ig preparation's oxygen
concentration can be determined using an electrode extending into
the container and into the Ig preparation contained therein.
Alternatively, the Ig preparation's oxygen concentration can be
determined after opening of the container. In this latter case,
determination is carried out within 5 minutes after opening of the
container in order to avoid corruption of the respective result by
an increase of the oxygen content of the gas which is in contact
with the immunoglobulin preparation.
Without wanting to be bound by the theory, it is assumed that the
yellowish coloration typically seen with conventional Ig
preparations is due to an oxidative alteration of the Ig contained
therein. According to the present invention, this oxidative
alteration is reduced by maintaining the amount of oxygen dissolved
in the preparation at a concentration lower than the concentration
that would be established if the preparation is stored under air at
atmospheric pressure.
Given the fact that according to the present invention an Ig
preparation can be obtained, which even after prolonged storage
shows only a slight yellowish coloration or no yellowish coloration
at all, both patients and physicians can readily acknowledge that
the Ig contained therein is in good quality, which further
contributes to an increase in the acceptance of the
preparation.
Apart from being indicative for a low degree of presumably
oxidative Ig alteration, a colourless or only slightly coloured
preparation is visually much more appealing than a yellow or a
yellow-brownish one.
A particularly high stability of the Ig preparation of the present
invention can be achieved if the concentration of oxygen dissolved
at room temperature is less than 175 .mu.mol/l, preferably less
than 150 .mu.mol/l, more preferably less than 125 .mu.mol/l, and
most preferably less than 100 .mu.mol/l.
Since for conventional Ig preparations, the effect of yellowish
coloration is particularly pronounced for preparations having a
high Ig concentration, the present invention particularly refers to
a preparation comprising Ig in a mass-volume percentage of at least
5%, preferably at least 10%, more preferably at least 12%, more
preferably at least 14%, more preferably at least 16%, more
preferably at least 18%, and most preferably at least 20%.
Preferably, the Ig preparation is a polyclonal Ig preparation, more
preferably a polyclonal IgG preparation.
Compliance of the Ig preparation with the respective coloration
requirements of the European Pharmacopoeia can be determined by the
respective method given therein (Ph. Eur. 5.5, 2006, General
methods 2.2.2 Degree of Coloration of Liquids).
Alternatively, compliance with the coloration requirements can also
be determined by a spectrophotometric method, the results of which
have been found to correlate with the results of the method
according to the European Pharmacopoeia. Specifically, it has been
found that an Ig preparation having a mean optical density
A.sub.350-500 nm (i.e. absorbance at 350 nm minus absorbance at the
reference wavelength 500 nm) of less than 0.355 fully complies with
the respective requirements of the European Pharmacopoeia.
When stored over 24 months at 25.degree. C. in the dark, a mean
increase of the optical density (absorbance) A.sub.350-500 nm of
only about 0.1 can be achieved according to the present invention,
when stored over 36 months at 25.degree. C. in the dark, a mean
increase of the optical density of only about 0.15 can be achieved
(corresponding to an approximate monthly increase of the absorbance
of 0.004). When stored over 3 months at 5.degree. C. under light
exposure, a mean increase of the optical density A.sub.350-500 nm
of only about 0.04 can be achieved according to the present
invention (corresponding to an approximate monthly increase of the
absorbance of 0.01), which is in clear contrast to the mean
increase for an Ig preparation in which the oxygen concentration is
not reduced according to the present invention, said increase being
about 1.2 (corresponding to an approximate monthly increase of the
absorbance of 0.40). Further, when stored over 6 months at
37.degree. C. in the dark, a mean increase of the optical density
A.sub.350-500 nm of only about 0.18 can be achieved according to
the present invention (corresponding to an approximate monthly
increase of the absorbance of 0.03), which is in clear contrast to
the mean increase for an Ig preparation in which the oxygen
concentration is not reduced according to the present invention,
said increase being about 0.24 (corresponding to an approximate
monthly increase of the absorbance of 0.04).
The Ig preparations of the present invention can be used both for
the intravenous and the subcutaneous administration to a patient,
by way of a non-limiting example for the treatment of PID or CVID.
The use for the subcutaneous administration is however
preferred.
Given the high concentration of Ig, the present invention allows
smaller volumes of the preparation to be administered to the
patient while maintaining the efficacy compared to conventionally
available preparations having a lower Ig concentration.
Since the Ig preparation according to the present invention is
preferably used for the subcutaneous administration to a human, the
present invention also relates to the use of the Ig preparation for
the preparation of a medicament for subcutaneous administration to
a human. As for example reported by S. Misbah et al, Clinical and
Experimental Immunology, 158 (Suppl. 1); pp. 51-59, there are
various advantages of the subcutaneous administration of the
preparation over the intravenous administration. In particular,
venous access is not required and the need for premedication with
corticosteroids and anti-histamines is reduced.
Also, when using the subcutaneous administration route the marked
peaks typically seen with monthly IVIg infusions are dampened and
persistently elevated Ig levels are obtained leading to a reduction
in systemic side effects.
Preferably, the Ig comprised in the Ig preparation of the present
invention essentially consists of IgG, but is in no way limited
thereto. According to other preferred embodiments of the
preparation of the present invention, the Ig comprises or
essentially consists of IgM or comprises or essentially consists of
IgA, respectively.
According to another aspect, the present invention further relates
to a storage system for an Ig preparation, preferably a polyclonal
Ig preparation, said storage system comprising a container having
an interior, a first portion of said interior being occupied by the
Ig preparation and the remaining second portion of said interior
forming a headspace and being occupied by a gas, wherein in the gas
of the headspace the content of oxygen is less than 20 vol-%. In
the context of the present invention, the term "vol-%" has the
meaning commonly used in the technical field and denotes the volume
ratio of the respective gas component in relation to the total
volume of the gas in which it is contained.
The gas in the headspace of the storage system of the present
invention thus has a reduced oxygen content compared to the
surrounding air. If stored in such a storage system, the oxygen
dissolved in the Ig preparation can thus be kept at a concentration
below 200 .mu.mol/l, preferably below 175 .mu.mol/l, more
preferably below 150 .mu.mol/l, even more preferably below 125
.mu.mol/l, and most preferably below 100 .mu.mol/l over a prolonged
storage period, and yellowish coloration can be vastly reduced even
if the Ig preparation is stored under light and at room
temperature.
Methods for determining the oxygen content in the gas of the
headspace are known to a skilled person. For example, the oxygen
content can be determined by laser absorption spectroscopy, in
particular tuneable diode laser absorption spectroscopy, thus
eliminating interference of other components contained in the
headspace gas. Specifically, the oxygen content can be determined
by means of a device of the type LaserGas.TM. II (LaserGas Oy,
Finland), whereby the absorption line of oxygen is scanned by means
of a single-mode diode. The absorption of light by the oxygen
molecules is measured by a detector, based on which the oxygen
content of the headspace gas can be calculated.
It is preferred that in the gas of the headspace the content of
oxygen is less than 16 vol-%, preferably less than 12 vol-%, more
preferably less than 10 vol-%, and most preferably less than 7
vol-%. An oxygen content of less than 7 vol-% has been found to be
particularly preferred, since Ig preparations stored under a
respective headspace in the container has been shown to fully
comply with the requirements of the European Pharmacopoeia even
after a prolonged storage period of 24 months or longer, even after
a storage period of 36 months or longer, even when stored at
25.degree. C. (in the dark), as will be shown in detail below.
According to a very straightforward and thus preferred embodiment,
the gas of the headspace is at least approximately at atmospheric
pressure.
It is further preferred that in the gas of the headspace the
content of inert gas is more than 80 vol-%, preferably more than 84
vol-%, more preferably more than 88 vol-%, more preferably more
than 90 vol-%, and most preferably more than 93 vol-%. The inert
gas may be e.g. nitrogen, argon, other noble gases or mixtures
thereof. Given its availability, nitrogen is preferably used.
It is further preferred that the container of the gas-tight storage
system comprises a vial, in particular a vial as standardized by
DIN/ISO 8362-1.
According to a further preferred embodiment, the volume ratio of
the headspace to the Ig preparation ranges from about 0.1:1 to
0.9:1, depending on the vial used. For a 6R vial, for example, the
ratio is typically about 0.9:1 whereas for a 20R vial, the ratio is
typically at about 0.1:1.
In particular, the storage system of the invention improves the
stability of an Ig preparation after a prolonged storage period of
24 months, even of 36 months, at room temperature in the dark. When
using a 20% Ig preparation as reference, the storage system of the
invention provides that the absorbance A.sub.350-500 nm of the
immunoglobulin preparation remains below 0.28 upon storage for 24
months at 25.degree. C. in the dark, preferably the absorbance
A.sub.350-500 nm remains below 0.355 when measured for a 20% Ig
preparation after storage for 6 months at 37.degree. C. in the
dark. The storage system of the invention provides a stable
immunoglobulin preparation showing an increase in A.sub.350-500 nm
of less than 0.18, preferably of less than 0.17, even more
preferably of less than 0.16, when stored at 25.degree. C. in the
dark for 36 months. The storage system of the invention provides a
stable immunoglobulin preparation showing an increase in
A.sub.350-500 nm of less than 0.22, preferably of less than 0.20,
even more preferably of less than 0.19, when stored at 37.degree.
C. in the dark for 6 months.
According to a further aspect, the present invention also relates
to a process for providing a storage system for an Ig preparation
comprising the steps that the Ig preparation is filled into a
container and the container is sealed, wherein prior to the sealing
the headspace of the container is filled with a gas such that the
oxygen content in the gas of the headspace is less than 20 vol-%,
preferably less than 16 vol-%, more preferably less than 12 vol-%,
even more preferably less than 10 vol-%, and most preferably less
than 7 vol-%. This "inert gassing" of the headspace allows the
concentration of the oxygen dissolved to be kept at a concentration
below 200 .mu.mol/l preferably below 175 .mu.mol/l, more preferably
below 150 .mu.mol/l, even more preferably below 125 .mu.mol/l, and
most preferably below 100 .mu.mol/l over a prolonged storage
period. Preferably, the prolonged storage period is longer than 24
months, preferably even longer than 36 months, at 25.degree. C. (or
room temperature) in the dark. In particular, the process of the
invention improves the stability of an Ig preparation after a
prolonged storage period of 24 months, even of 36 months, at room
temperature in the dark. When using a 20% Ig preparation as
reference, the process of the invention provides that the
absorbance A.sub.350-500 nm of the immunoglobulin preparation
remains below 0.28 upon storage for 24 months at 25.degree. C. in
the dark, preferably the absorbance A.sub.350-500 nm remains below
0.355 when measured for a 20% Ig preparation after storage for 6
months at 37.degree. C. in the dark. The process of the invention
provides a stable immunoglobulin preparation showing an increase in
A.sub.350-500 nm of less than 0.18, preferably of less than 0.17,
even more preferably of less than 0.16, when stored at 25.degree.
C. in the dark for 36 months. The process of the invention provides
a stable immunoglobulin preparation showing an increase in
A.sub.350-500 nm of less than 0.22, preferably of less than 0.20,
even more preferably of less than 0.19, when stored at 37.degree.
C. in the dark for 6 months.
Preferably, the gas of the headspace of the storage system obtained
is at atmospheric pressure.
Alternatively or additionally to the above process, an Ig
preparation defined above with a reduced concentration of oxygen
dissolved can be obtained by subjecting the Ig preparation or its
solvent to a degassing step and/or a gassing step using an inert
gas. It is thereby preferred that the solvent of the Ig
preparation, typically water, is subjected to the degassing and/or
gassing step prior to the formulation of the Ig preparation.
Degassing can for example be obtained by storing the solvent at an
elevated temperature or at a reduced pressure. Gassing using an
inert gas can for example be performed by introducing the inert gas
into the respective preparation or its solvent.
In accordance with the above, the present invention relates
according to a further aspect also to the use of a gas having an
oxygen content of less than 20 vol-% for increasing the storage
stability of an immunoglobulin preparation comprising
immunoglobulin in a mass-volume percentage of at least 4%. As given
above, the gas is thereby preferably used in the headspace of a
container in which the Ig preparation is stored.
With the storage system of the invention, or the process of the
invention, or the use of a gas with an oxygen content of less than
20% according to the invention, a reduction in the mean increase of
absorbance at 350nm for an Ig preparation of at least 10% is
achievable, preferably of more than 12%, 14%, 16%, 18% or 20%, more
preferably of more than 25%, 30%, 35%, 38%, 40%, or even 45% can be
achieved when stored for a prolonged period in the dark. With the
storage system or process of the invention, this can be achieved
for preparations comprising Ig in a mass-volume percentage of at
least 5%, preferably at least 10%, more preferably at least 12%,
more preferably at least 14%, more preferably at least 16%, more
preferably at least 18%, and most preferably at least 20%.
A detailed description of a process according to the present
invention is given in the example below.
EXAMPLES
Ig preparation
The technical effect achieved by the present invention was assessed
using IgPro20.
IgPro20 is a ready-to-use, 20% (200 g/l) liquid preparation of
polyvalent human IgG for subcutaneous administration, manufactured
from large pools of human plasma. Its protein moiety is .gtoreq.98%
IgG, of which over 90% is in the form of monomers+dimers. IgPro20
is formulated with the stabilizer L-proline (250 mmol/L) at pH 4.8
without preservatives.
Filling of the Ig Preparation
During aseptic filling of IgPro20 into a vial, the headspace of the
vial was gassed with nitrogen.
Specifically, gassing with nitrogen was carried out in two steps:
a) directly after introducing the Ig preparation into the vial,
sterile-filtered nitrogen gas was filled into the headspace by
means of an inflation needle extending into the headspace; b)
during insertion of the plug for sealing the vial, nitrogen gas was
blown onto the opening of the vial by a further inflation needle
extending in angular direction with regard to the axis of the
opening.
The nitrogen gas used was sterile-filtered using a sterile filter
of the type KA02PFRP8 of Pall Corporation. The operating pressure
of the gassing equipment was set to about 0.5 bar.
By the above procedure, a storage system can be provided having a
headspace which immediately after sealing of the vial has an oxygen
content of less than 4.5 vol-%. Given the fact that the preparation
is not degassed or gassed with an inert gas before filling into the
vial, the oxygen content in the gas of the headspace might increase
until an equilibrium between the immunoglobulin and the gas is
established. Even in this case, the content of oxygen remains below
7 vol-%.
Storage Conditions
The storage conditions and test intervals of the long-term
stability program for IgPro20 were chosen according to the
International Conference on Harmonization (ICH) of Technical
Requirements for Registration of Pharmaceuticals for Human Use
guideline Q1A(R2). Long-term storage for up to 24 months at
25.degree. C. is shown in FIG. 3 below.
In order to simulate secondary packaging, the vials were stored at
a temperature of 37.degree. C. in the dark.
A horizontal position of the container maintained contact of the
solution with the stopper, in accordance with ICH guideline
Q5C.
Quantification of Yellowish Coloration
In order to quantify yellowing of the Ig preparation, its mean
optical density at 350 to 500 nm has been determined after several
intervals of storing. This is based on the finding that the mean
optical density can be correlated to the standardized examination
of the coloration of liquids as described in the European
Pharmacopoeia (Ph. Eur. 5.6, January 2005, General methods 2.2.2,
Degree of Coloration of Liquids).
The technical effect achieved by the present invention is
illustrated by way of the attached figures, of which
FIG. 1 is a graphical representation of the optical density
(absorbance) A.sub.350-500 nm of the Ig preparation stored as a
function of storage time after storage at 5.degree. C. under light
without inert gassing of the headspace (diamonds), using a gas in
the headspace having an oxygen content of 16 vol-% (squares), 12
vol-% (triangles), 10 vol-% (crosses), 7 vol-% (stars) and less
than 7 vol-% (circles), respectively; and
FIG. 2 is a graphical representation of the optical density
(absorbance) A.sub.350-500 nm of the Ig preparation stored as a
function of storage time after storage at 37.degree. C. in the dark
without inert gassing of the headspace (diamonds) and using a gas
in the headspace having an oxygen content of at most 7 vol-%
(squares), respectively, and
FIG. 3 is a graphical representation of the mean optical density
(absorbance) A.sub.350-500 nm of a number of samples of the Ig
preparation as a function of storage time when stored at 25.degree.
C. in the dark using a gas in the headspace having an oxygen
content of less than 7 vol-%.
As can be seen from FIG. 1, yellowing of the immunoglobulin
preparation overtime is reduced by using a gas having a reduced
oxygen content (and thus also a reduced oxygen partial pressure) in
the headspace. Specifically, by using a gas having an oxygen
content of less than 7 vol-%, the optical density A.sub.350-500 nm
is less than 0.35 even after storage for 6 months, thus fully
complying with the requirements of the European Pharmacopoeia after
prolonged storage. The concentration of oxygen dissolved in the
respective sample at room temperature is less than 100
.mu.mol/l.
Referring to FIG. 2, a mean increase of the optical density
A.sub.350-500 nm of only about 0.18 can be achieved according to
the present invention when stored over 6 months at 37.degree. C. in
the dark using a gas in the headspace having an oxygen content of
at most 7 vol-%. This is in clear contrast to the mean increase for
an Ig preparation stored without gassing of the headspace, said
increase being about 0.24.
As shown in FIG. 3, a mean increase of the mean optical density
A.sub.350-500 nm of only about 0.1 can be achieved according to the
present invention when stored over 24 months at 25.degree. C. in
the dark.
As shown in Table 1 below, the mean optical density is still below
0.355 even after storage over 36 months at 25.degree. C. in the
dark, and even lower if stored at 5.degree. C. in the dark. The
values of 6 different lots are shown.
TABLE-US-00001 TABLE 1 25.degree. C. 5.degree. C. 30 months 36
months 30 months 36 months O.sub.2 O.sub.2 O.sub.2 O.sub.2
.mu.mol/L % O.sub.2 A.sub.350 .mu.mol/L % O.sub.2 A.sub.350
.mu.mol/L % O.sub.2 A.sub.350 .mu.mol/L % O.sub.2 A.sub.350 79.2
6.3 0.270 83.5 6.6 0.319 61.3 4.8 0.156 58.4 4.6 0.158 75.8 6.0
0.229 79.9 6.3 0.249 56.0 4.4 0.132 54.8 4.3 0.130 82.4 6.5 0.297
86.3 6.8 0.332 65.3 5.1 0.181 62.4 4.9 0.186 53.3 4.2 0.298 54.3
4.3 0.289 66.0 5.2 0.155 62.3 4.9 0.159 55.7 4.4 0.231 57.3 4.5
0.244 62.3 4.9 0.133 58.5 4.6 0.131 54.7 4.3 0.290 56.3 4.4 0.318
63.5 5.0 0.180 59.8 4.7 0.179
Table 2 shows the mean monthly increase in absorbance A.sub.350-500
nm in different storage conditions. For all conditions tested,
keeping the oxygen concentration below 100 .mu.mol/l, or below 7%
oxygen in the headspace, leads to significantly lower increase in
absorbance, indicating significantly higher stability of the IgG
preparation. All samples were stored in the dark. Data were
collected for 24 or 36 months: during this time, the increase of
absorbance over time was about linear.
TABLE-US-00002 TABLE 2 Mean monthly A.sub.350-500 nm Storage Oxygen
in increase in reduction temperature headspace A.sub.350-500 nm by
O2 reduction 37.degree. C. <7% 0.030 42.5% 20% (air) 0.052
25.degree. C. <7% 0.0042 19.9% 20% (air) 0.0052 5.degree. C.
<7% 0.00037 47.8% 20% (air) 0.00071
* * * * *